2,3,5,6-Tetrahydro-5-(indol-3-yl)-1H-pyrrolo{8 2,1-b{9 {8 1,3{9 benzodiazepines and their preparation

ABSTRACT

2-(2- or 3-Indolyl)indolines, unsubstituted and carbon substituted, condense with N-mono substituted carboxamides or with lactams under the influence of phosphorus oxychloride to produce 1-(N-substituted iminoalkyl)-2-(2- or 3indolyl)indolines. The 2-(3-indolyl)-1-(2-(1pyrrolinyl))indolines rearrange to produce benzodiazepine derivatives. These products have diuretic activity on oral administration.

United States Patent [191 Wu et al.

[ 2,3,5,6-TETRAHYDRO-5-(lNDOL-S-YL)-1H- PYRROLO[ 2,1-B[1,3]BENZODIAZEPINES AND THEIR PREPARATION [75] Inventors: Yao Hua Wu;Arthur Jacob Mueller, both of Evansville, Ind.

[73] Assignee: Mead Johnson & Company,

Evansville, Ind.

[22] Filed: May 6, 1974 [21] Appl. No.: 467,432

Related US. Application Data [60] Division of Ser, No. 251,059, May 8,1972, Pat. No. 3,829,414, which is a division of Ser. No. 4,108, Jan.19, 1970, Pat. No. 3,697,553, which is a continuation-in-part of Ser.No. 709,941, March 4, I968, abandoned.

[52] US. Cl... 260/326.15; 260/239 B; 260/239 BC;

260/326.ll R; 260/296 B; 424/274 [51] Int. Cl C07d 27/56 [58] Field ofSearch 260/326.l5

[ July 15, 1975 [56] References Cited UNITED STATES PATENTS 3,679,7027/1972 Wu et al. 260/326.l5

Primary ExaminerElbert L. Roberts Assistant Examiner-S. P. WilliamsAttorney, Agent, or Firm-Robert E. Carnahan; Robert H. Uloth 5 7]ABSTRACT 5 Claims, No Drawings 12,3,5,6-TETRAHYDRO--(INDOL-3-YL)-1H-PYR- ROLO[2,l-B][1,3]BENZODIAZEPINESAND THEIR PREPARATION CROSS REFERENCE TO RELATED APPLICATIONS Thispatent application is a divisional of U.S. patent application Ser. No.251,059 filed May 8, .1972, now U.S. Pat. No. 3,829,414, which in turnis a divisional of U.S. patent application Ser. No. 4108 filed Jan. 19,1970 and now U.S. Pat. No. 3,697,553 patented Oct. I0, 1972 which inturn is a continuation-in-part of U.S. patent application Ser. No.709,941 filed Mar. 4, 1968 and now abandoned.

FIELD OF THE INVENTION Three related series of novel nitrogenheterocyclic compounds have been prepared by reaction of indole dimerswith N-substituted carboxamides having a single carboxamide hydrogenatom. The invention involves the discovery that these substances havediuretic activity and includes processes for their synthesis and use asdiuretic agents.

DESCRIPTION OF THE PRIOR ART Indole and skatole and various othersubstituted indoles are known to dimerize under strongly acidicconditions to produce 2-(2- or 3-indolyl)indolines. Refer to B. Oddo, etal. Chem. Abstracts 19, 65 (1926); O. Schmittz-Dumont, Ann. 514, 267(1934); O. SchmittzDumont, et al., Ber. 66, 766 (1933); H. F. I-Iodson,et al., J. Chem. Soc. 3544 1951); and G. Berti, et al., TetrahedronLetters No. 26, 13 (1960). These substances have been described in theliterature largely as a result of basic studies on the chemistry ofindole. They have not heretofore been found to be of utility in thefield of medicinal chemistry.

The thiazide diuretics typified by 6-chloro-7- sulfamoyl-l,2,4-benzothiadiazinel l -dioxide chlorothiazide) have largely replacedthe organo mercurial compounds which were introduced as diuretics nearly50 years ago-Both are unrelated chemically to the substances of thisinvention. More recently other types of organic compounds have beenreported as diuretic agents. They include 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid (furosemide), 2,4,7-triamino-6-phenylpteridine (triamterene) and certain steroid compoundswhich are aldosterone antagonists. Each of these also belongs to adifferent chemical class than the substances of the present invention.

SUMMARY OF THE INVENTION The novel substances of the present inventionhave the following formulas.

Formula I 6 l R -fi RN Formula II Formula III The ring positions arenumbered in Formulas I and III for nomenclature purposes. The positionnumbers for Formula II are the same as for Formula I.

In Formulas I, II, and III R, R and R may be hydrogen, halogen, alkylhaving 1 to 4 carbon atoms, alkoxy having I to 12 carbon atoms, aralkoxyhaving 7 to 12 carbon atoms, alkanoyl having 2 to 4 carbon atoms, nitro,or cyano.

In Formula I, R is hydrogen or alkyl having 1 to 4 carbon atoms and R isalkyl having 1 to 8 carbon atoms, or cycloalkyl or polycycloalkyl having3 to 10 carbon atoms. R and R may be joined to form a 2-( lpyrrolinyl)group which may be carbon substituted by up to 3 alkyl groups eachhaving from 1 to 4 carbon atoms.

In Formula II, R is hydrogen or alkyl having 1 to 4 carbon atoms. R isalkyl having from 1 to 8 carbon atoms or cycloalkyl or polycycloalkylhaving 3 to 10 carbon atoms. R and R may be joined to form aheterocyclic function having a 5, 6, or 7 membered ring which in turnmay be carbon substituted by up to 3 alkyl groups having from 1 to 4carbon atoms.

In Formula III, R, R, and R may be hydrogen atoms or lower alkyl groupshaving from 1 to 4 carbon atoms. R is located in either the lor2-positions.

The term polycycloalkyl is intended to refer to an alicyclic substituenthaving up to 10 carbon atoms and more than one ring such as adamantyl.

The present invention also includes the acid addition salts of thecompounds of Formulas I, II, and Ill. Pharmaceutically acceptable acid.addition salts are, of course, selected when the product is to be usedas a medicinal agent. For synthesis and purification purposes, however,salts ofacids which are not'pharmaceutically acceptable are sometimesuseful. For example, for resolution studies, acids such asd-camphorsulfonic acid or other optically active acid may be selectedfor preparation of diasteroisomeric salts according to conventionalresolution methods. In other instancessalts with acids which are notpharmaceutically acceptable may is illustrated in the followingequations. The substances of Formula II] are prepared by rearrangementfrom certain Formula I compounds. The substituents R, R R, R R R, and Rhave the same meanings as previously defined.

be founduseful as intermediates in synthesis of the 5 5 I. u R R I a \N/-R R-mrc-R r ula I Formula 1v cu c11 I a R5 H v R-Nnc-R" Formula II l lt H H Formula V pharmaceutical end products for instances when they havedesirable crystallization properties.

The pharmaceutically acceptable acid addition salts are those in whichthe anion does not contribute significant toxicity to the salt in thedosages employed in accordance with the present invention. Examples ofsuitable salts are the acetate, propionate, butyrate, pamoate, tannate,mucate, citrate, maleate, tosylate, mesylate, phosphate, nitrate,sulfate, hydrobromide, hydroiodide, hydrochloride, etc. salts.

The compounds of the present invention have one, two, or more asymmetriccarbon atoms and consequently, exist in a number of stereoisomericforms. Those of Formula I have an asymmetric carbon atom in the2-position of the indoline ring. Those of Formula II have asymmetriccarbon atoms at both the 2- and 3- positions of the indoline ring. Thoseof Formula III have an asymmetric carbon atom in the 5-position. R', RR, R", R, R R R R", and R and the pyrrolidine ring of Formula III maycontain additional asymmetric centers. Purified racemic modificationsand optical isomers of a given individual structural type have diureticpotencies not substantially different from other stereoisomeric forms ofthe same structural type. Accordingly, it is intended to include each ofthe stereoisomeric forms of the structures referred to herein within thepresent invention. In some instances, one or the other of the variousstereoisomers may be preferred for pharmaceutical purposesby virtue ofother properties which are unique.

DETAILED DESCRIPTIONOF THE INVENTION CHEMICAL SYNTHESIS The compounds ofFormulas I and II are prepared by reaction of an indole dimer of FormulalV;or a skatole dimer of Formula V respectively with a carboxamide asFrom 1 to 2 molecular proportions of the carboxamide and one molecularproportion of the indole or skatole dimer are dissolved or suspended inan inert solvent and treatedwith substantially one molecular proportionof phosphorus oxychloride. The aprotic, water immiscible solventsincluding the liquid hydrocarbons, chlorinated hydrocarbons and ethers,including 1,2- dichloroethane, chloroform, carbon tetrachloridegdiethylether, 'di-(n-butyl) ether, benzene, hexane, etc. are preferred. Themode of addition is not critical, that is, a solution or suspension ofthe indole dimer and carboxamide may be added to a solution of thephosphorus oxychloride, or a solution of the phosphorus oxychloride inthe solvent may be added to a solution of the other reactants. Thereaction takes place in a facile manner and it does not requireprolonged periods for completion. Reaction temperatures in the range ofabout 20C. up to about 40C. are operable. The process is exothermic and,accordingly, external cooling is generally necessary to maintain thereaction mixture within the foregoing temperature range. For convenienceand economy temperatures approximating room temperature are preferred.Efficient stirring is desirable. Reaction times of the order of fromabout 1 to 15 hrs. are employed.

The product is recovered by pouring the reaction mixture into an aqueoussolution of a base, or into water to hydrolyze the reaction complex. Theproduct is extracted into the organic solvent layer. It is preferred toemploy water immiscible solvents to facilitate isolation of the reactionproduct. The product is then recovered from the solvent extract byevaporation and crystallization. Acid addition salts are prepared inconventional fashion by treatment of the free base form of the product,preferably in solution, with the desired acid. Organic solvents such asethanol and ether are preferred for the preparation of the acidadditionsalts since they crystallize from these solvents.

The indole or skatole dimer staring materials may be prepared in situand used without isolation if desired employing the corresponding indoleor skatole as raw material. This mode of operation, however, generallyaffords lower yields and is not preferred. Reaction yields according tothe preferred method are generally of the order of or greater.

With respect to preparation of the substances of Formula I wherein R andR are joined to form the 2- pyrrolinyl group (as shown in Formula VI)which may be substituted by from 1 to 3 alkyl groups, certainprecautions are desirable in application of the foregoing method due tothe fact that these substances when in the free base form are subject torearrangement into the 2,3,5 ,6-tetrahydro-5-(indol-3-yl)- 1 H-pyrrolo[2, 1

b][l,3]benzodiazepines of Formula III. This is illustrated by thefollowing equation.

In Formula VI, R, R R R R, and R have the same meaning as previouslystated. The propensity for the substances of Formula VI to undergo therearrangement is inversely related to the number of alkyl groups in thepyrrolinyl ring, R, R", and R. In those instances where each of R R",and R are hydrogen atoms or only one of them is alkyl, rearrangement tothe benzodiazepine structure, Formula III, occurs on warming the freebase Formula VI in ethanol. Thus, attempts to recrystallize thesubstances of Formula VI frequently leads to rearrangement. When R and Rare each alkyl groups in the substance of Formula VI, heating forprolonged periods of the order of hrs. in refluxing butanol is necessaryto effect rearrangement.

The rearrangement is facilitated by polar solvents and particularly theprotic solvents including the lower alkanols. In some instances therearrangement takes place thermally. For example, when R R, and R arehydrogen atoms heating at 180C. in the absence of a solvent brings aboutthe rearrangement. On the other hand, when R and R are methyl groups andR is a hydrogen atom the substance is thermally stable up to 300C.

As a general statement the preferred method for the preparation of thebenzodiazepine of Formula III involves heating a solution of theindolylindoline of Formula VI in a protic solvent for a period of fromabout 1 to 60 hrs. at a temperature of from about to 150C. andpreferably from about to C. Preferred solvents are the alkanols andpolyols having up to about 6 carbon atoms. Conversely in preparing anindolylindoline of Formula VI, the foregoing conditions should beavoided. None of the substances of Formula II nor those of Formula I inwhich R is hydrogen or I alkyl and R is alkyl, cycloalkyl, orpolycycloalkyl are subject to the rearrangement described for thecompounds of Formula VI.

The substances of Formula III are novel compounds which have been fullycharacterized as to structure and properties. Generally speaking theyare less soluble and thus somewhat less tractable for pharmaceuticalpurposes than their counterparts of Formula I. This reduced solubilityfacilitates their separation from synthesis mixtures resulting from therearrangement procedure, and their purification by crystallization. Theyare active diuretic agents and are therefore considered part of thepresent invention. They form acid addition salts and exist in variousstereoisomeric forms just as do the substances of Formula I.

PHARMACOLOGY The compounds of Formulas I, II and Hi are diuretic agentswhich are orally effective in mammalsand char- Formula III acterized byhigh potency with reference to the thiazides and mercurial diuretics.The presence of an effective amount of many of these substances in themammalian circulatory system has the added benefit of affording aprotective antithrombogenic and cardiac antiarrhythmic effect.

Urine flow, sodium excretion and chloride excretion are increasedfollowing oral or parenteral administration of the substances ofFormulas I, I] and III; bicarbonate excretion is unchanged. Withpreferred members of the series, potassium excretion is unchanged orreduced. The disadvantages associated with prior widely used diureticsare believed to stem largely from a lack of one or more of the foregoingcharacteristics. For example, the thiazides cause an increased excretionof potassium. The mercurials must be administered by injection. Otheragents which do not suffer from those disadvantages lack the potency ofthe present substances.

The diuretic properties have been examined for a large number of thecompounds of Formulas I, II and III in studies in rats. Detailed studiesin dogs have confirmed the rat findings, and have shown that thediuretic effects are the result of a different mechanism of action fromthat of currently popular diuretics such as hydrochlorthiazide,triamterene, and mercaptomerin (a mercurial). Use of the substances ofFormulas I, II and III in combination with other diuretics and, moreparticularly, their applicability in instances where lack of response toother diuretics is encountered is therefore suggested.

The substances of Formulas I, II and III exert their optimum effectswhen administered to mammals in non-toxic doses ranging from about 0.1to 25 mg./kg.

of body weight per day. In mice, doses in the range of from 25 to 1000mg./kg. of body weight administered orally are without are undesiredeffects whatsoever, and the letal doses (ALD for mice treated orally arefrom 2 to 10 or more times larger. ALD values for mice treated orallyare in the range of 50 to 2000 mg./kg. The substances may beadministered orally or parenterally but the oral route is preferred andis nearly always applicable due to the prompt onset of action of thepresent compounds.

Evaluation of the diuretic action may be made by the method ofLipschitz, et al. (Jour. Pharma. & Experi. Thera. 79, 97 (1943)).According to this method, fasted rats are hydrated orally with mg./kg.of body weight of isotonic saline solution after arranging them intogroups of 8 for dosing. The saline solution serves as the vehicle fordosing. One control group receives a dose of 960 mg./kg. of body weightof urea, and the effects of the medications used in the other groups arerelated to it. The animals of two further groups receive doses,preferably at different levels, of a standard reference diuretic agentsuch as hydrochlorthiazide. The animals of all remaining groups aretreated with various doses of the test substance. Immediately aftertreatment, the animals are placed in metabolism cages (two rats of thesame group per cage) and left without food or water for 5 hours. Thevolume of urine excreted by each pair is determined after this periodand the urines are analyzed for sodium, potassium, and chloride. Theresults for the test drugs are expressed as ratios of the volume ofurine or total quantities of electrolytes excreted during theexperimental period to the values observed for the urea control group.

The compounds of Formulas I, II and III were administered in oral dosesin the foregoing test over the range of 3.1 to 50.0 mg./kg. of bodyweight. The maximum diuresis achieved with hydrochlorthiazide which wastested for comparison occurred at a dose of 12.5 mg./kg. of body weight,and was approximately 1.5 fold that of urea. With few exceptions thesubstances of Formulas I, II and III described in the following examplessubstantially exceeded this degree of activity. In general, at themaximally effective dose of each, the amount of potassium excreted wasless than that excreted by the hydrochlorthiazide controls and in manyinstances less than that excreted by the urea controls.

In the dog almost instantaneous diuresis occurred on intravenousinjection of 2 mg./kg. of 2,3,5,6-tetrahydro-5-(indol-3-yl)-lI-I-pyrrolo[2,1- b][l,3]benzodiazepine.Continuous intravenous infusion at the rate of 2 mg./kg. per hourthereafter afforded maximal diuretic effect.

The antithrombogenic activity of the substances of Formulas I, II andIII is evident on evaluation thereof according to the method of Born,Nature 194, 927 (1962) or OBrien, J. Clin. Path. 15, 446 (1962). This isa nephelometric method in which the change in turbidity of a specimen ofplatelet rich blood plasma is measured on causation of plateletaggregation by addition of a thrombogenic agent such as adenosinediphosphate, epinephrine, serotonin, or a long-chain saturated fattyacid. In the evaluation of the present substances adenosine diphosphateis an appropriate thrombogenic agent. An increase in transmittance oflight occurs when the thrombogenic agent is added to the specimen ofplatelet rich plasma due to clumping of the platelets. Efficacy of atest compound is determined by its ability to prevent this clumping andconcomitant increase in transmittance. With active compounds variousconcentrations are tested and that concentration causing a 50% reductionin the thrombogenic response is determined from a concentrationresponsecurve. The resulting figures are convenient for comparing the activityof various compounds. Significant activity was exhibited in this testwith the products of Examples 1, 3, 7, 9, 11-19, 22, 25, 28,29, 36, and39. These substances at concentrations of the order of 50 meg/ml.reduced the thrombogenic capacity of adenosine diphosphate, 2 mcg./ml.by 50% or more.

Antiarrhythmic activity is evaluated in mice weighing 18 to 25 g.treated intraperitoneally with the test compound according to the methodof Lawson, J. Pharmacol. Exp. Therap. 160, 22, (1968'). According tothis test cardiac arrhythmia is induced by causing the mouse to inhalechloroform until respiratory arrest occurs. The ability of a testcompound to forestall the concomitant cardiac arrhythmia is measured bypretreatment of the animals with the substance by intraperitonealinjection and observation of the heart for arrhythmia visually throughan incision made after respiratory arrest occurs. The substances ofExamples 17, 28, 29, and 30 exhibited anti-arrhythmic capacitycomparable to that of quinidine sulfate. Anti-arrhythmic activity isalso demonstrable in the test for the products of Examples7,12,14,15,18,19, 21, 25, 31, 33, 34, and 37.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 2-(3-Indolyl)-1-[2-(1-pyrro1inyl)]indoline hydrochloride A mixture of 23.43 g. (0.1 mole) of2-(3-indolyl)- indoline and 17.02 g. (0.2 mole) of 2-pyrrolidone in 150ml. of 1,2-dichloroethane is treated with a solution of 15.33 g. (0.1mole) of phosphorus oxychloride in 50 ml. of 1,2-dichloroethane in onelot. The reaction temperature rises to 54C. and then cools to 30C.during a period of about 1% hrs. The mixture is then cooled to icetemperature in an ice bath and treated with ml. of ice water. Theorganic solvent layer is drawn off and the aqueous layer containing somesuspended solid is extracted with 50 ml. of dichloroethane. The combineddichloroethane solutions are then dried over anhydrous sodium sulfateand the solvent removed by distillation yielding a solid residueweighing 18 g. (31%). This is the crude hydrochloride salt of thedesired product. It is purified by recrystallization from a mixture of15 ml. of methanol and 50 ml. of isopropanol; yield 6.92 g.

The aqueous portion of the reaction mixture is then treated with 84 ml.of concentrated ammonium hydroxide (29%) and the mixture extracted withml. of dichloroethane. The dichloroethane extract is dried, andconcentrated to one-sixth of its original volume and diluted with 150ml. of low-boiling petroleum ether to yield 16.6 g. of a low-meltingsolid which is a crude form of the desired product in free-base form.For further purification, this material is converted to thehydrochloride salt by treatment thereof in ml. of ethanol with hydrogenchloride. The hydrochloride precipitates from the ethanolic solutionafter treatment with 200 ml. of ether; yield 15.9 g. (27.5%). A portionof the combined hydrochloride salts, weighing 22.8 g. is refluxed with540 ml. of ethanol to effect solution, allowing the solution to cool,and collecting the crystalline product which separates, yield 12.4 g.,m.p. 213.52l5.5C. Further quantities of the product may be recovered byconcentration of the filtrate.

Anal. Calcd. for C l-l, N .HCl: C, 71.09; H, 5.97; Cl, 10.50; N, 12.44.Found: C, 71.05; H, 6.02; Cl, 10.49; N, 12.30.

EXAMPLE 2 2-( 3-lndolyl)- l -[2-( l-pyrrolinyl)]indoline A sample of theproduct of Example 1, 0.9 g., is converted to the free base form bysuspending it in 100 ml. of water and adjusting the solution of analkaline pH with 40% aqueous sodium hydroxide. The base precipitates andis collected on a filter. It is recrystallized from isopropyl ether,m.p. l59161C.

Anal. Calcd. for C H N C, 79.70; H, 6.36; N, 13.94. Found: C, 79.56; H,6.83; N, 13.82.

Ultraviolet absorption maxima (methanol); 289 mp. (11,740), 265 mp.(617,850).

Infrared absorption maxima (5% in potassium bromide) occur at: 6.20,6.31, 6.74, 6.86, 7.05, 8.14, 8.60, 9.02, 9.49, 9.89, and 13.43;!"

The nuclear magnetic spectrum measured on a solution of this compound indeuterochloroform with tetramethylsilane as reference has the followingcharacteristics.

Table 1.

NMR Characteristics Example 2 EXAMPLE 32,3,5,6-Tetrahydro-5-(indol-3-yl)-lH-pyrrolo-[2,1- b] 1,3]benzodiazepine The same reactants are employed as in Example 1. Theyare mixed in the same way and then cooled to ice temperature after areaction period of about 1 hr. The mixture is then poured into 300 ml.of concentrated aqueous ammonium hydroxide (29%) containing 100 g. ofcrushed ice with stirring. The clear aqueous layer is separated, washed,once with ml. of 1,2- dichloroethane and the combined 1,2-dichloroethanesolutions containing the product dried over anhydrous magnesiumsulphate. The solution is concentrated to a thick residue which isdissolved in ml. of 80% ethanol. This solution is concentrated byboiling on a steam bath for about 1 hr. and allowing the solvent toevaporate until crystallization commences. It is at this stage thatrearrangement of the substance described in Example l to thepyrrolobenzodiazepine structure occurs. The product weighing 13.4 g.(45%) is collected after crystallization is complete, m.p. 234238C.;after recrystallization from absolute ethanol, m.p. 234-236C.

Anal. Calcd. for C l-l N z C. 79.70; H, 6.36; N, 13.94. Found: C, 79.80;H, 6.67; N, 13.95.

Infrared absorption maxima (5% in potassium bromide) occur at: 6.30,6.41, 6.85, 7.0, 7.14, 7.40, 7.71, 7.87, 8.26, 8.83, 9.17, 13.06, andl3.52p..

The nuclear magnetic resonance spectrum measured as a 10%(weight/volume) solution in trifluoroacetic acid with 2%tetramethylsilane added as an internal reference revealed the followingchemical shifts (r or 6) and coupling constants (.1).

Table 2.

Chemical Shift R ative Structural r 8(ppm) Area Multiplicity Feature0.52 9.48 1 Broad singlet NH 2.29 7.71 1 Doublet of doublets Aromaticring protons 2.9 7.1 7 Multiplet 3.32 6.68 1 Sharp singlet --CH-- 4.375.63 l Triplet .l=4.0 cps CH 5.93 4.07 2 Triplet .l=7.2 Cps "CH 6.373.63 2 Doublet J=4.0 cps CH 6.52 3.48 2 Triplet .l=8.3 cps CH 7.66 2.342 Multiplet Cl"l S-position of the pyrrolobenzodiazepine ring Z-positionof the indole ring El-position of the pyrrolobenzodiazepine ring(J-position of the pyrrolobenzodiazepine ring l-position of thepyrrolobenzodiazepine ring "Lposition of the pyrrolobenzodiazepine ringThe nuclear magnetic resonance spectra of the products of Examples 2 and3 illustrate certain key features which are typical of the substances ofthis invention and which are useful in distinguishing an indolylindolineof Formula 1 (Examples 2 and Table 1) from the correspondingpyrrolobenzodiazepine of Formula 111 (Example 3 and Table 2). Referringto Table l, the chemical shift at 8.20 ppm comprised of a doublet ofdoublets is a consequence of the deshielding effect of the pyrrolinegroup on the aromatic proton in the 7- position. This down field shiftof one of the aromatic proton signals is characteristic of theindolylindolines of Formula I. The l-l-7 chemical shift is evident inthe nmr spectra of each of the substances:o f Formula I and.

is in the range of 7.6 to 8.2 ppm. The nmr spectra of the acid additionsalts do not-reflect the H-7down field shift. I 1

A second key point is thedoublet of doublets appearing at 5.71 ppm inthe'spectrum of Example 2 (Table 1). The spacing of these peaks in suchthat one doublet exhibits a high coupling constant; usually near cps,and the other a low coupling constant. This is the result of thestereochemical relationship between the hydrogen ator'ns in the 2- and3-positions of the indoline ring. one of those in the 3-position beingnearly eclipsed with that in the 2-position resulting in a high couplingconstant. The corresponding chemical shift in the pyr-'rolobenzodiazepines appears as a doublet of doublets with nearlyequivalent coupling constants in some instances appearing as a triplet.This is due to the fact that more nearly equivalent interaction betweenthe C-5 and C-6 hydrogen atoms is possible in the benzodiazepine. Thisfeature is reported as a triplet at 5.63 ppm (.l=4.0 cps) in thespectrum of Example 3 (Table EXAMPLE 4 2 ,3 ,5,6-Tetrahydro-5-(indol-3-yl)-1H-pyrrolo-[2,1-

][ 1,3]benzodiazepine hydrochloride A portion of the product of Example3, 12 g., is suspended in 150 ml. of absolute ethanol and treated withone chemical equivalent of 5.02 N ethanolic hydrogen chloride. A clearsolution results which is diluted with 200 ml. of anhydrous etherresulting in precipitation of the desired hydrochloride salt. The saltis collected on a filter and recrystallized from a mixture of 150 ml. ofethanol and 150 ml. of ether, yielding 9.3 g. (69.1%) of pure product,m.'p. 262-264"C.

Anal. Calcd. for C H, N .HCl: C, 71.09; H, 5.97; Cl, 10.50; N, 12,44.Found: C, 71.38; H, 5.90; Cl, 10.26;

A mineral oil suspension of the substance exhibits the followingabsorption maxima in the infrared: 6.04 (characteristic of the amidiniumgroup at the 4-1 1 position of the ring), 6.21, 6.30, 7.74, 8.14, 8.68,9.04, 9.67, 12.86, 13.01, 13.31, and 13.41/.L. In the ultraviolet asingle peak is exhibited: Mu 2 M EXAMPLE 5 2,3 ,5,6-Tetrahydro-5-(indol-3-yl)-3-methyll H-pyrrolo[ 2, l -b][1,3]benzodiazepine The procedure of Example 3 is repeated substituting0.2 moles of 5-methyl-2-pyrrolidone for the 2- pyrrolidone specified inExample 3. The product is recovered in the fashion described there andrecrystallized from 80% aqueous ethanol, m.p. 190-192C.

Anal. Calcd. for C H N C, 79.97; H, 6.71; N, 13.32. Found: C, 79.80; H,6.87; N, 12.93. p

The nuclear magnetic resonance spectrum of this substance measured indeuterodimethylsulfoxide with tetramethylsilane as reference exhibitsthe following characteristics.

2,3,5 ,6-Tet rahydro-5-(indol-3-yl)-3-methyl-lH-pyrrolo[2',1-b][1,3]benzodiazepine hydrochloride The product of Example 5 is convertedto the hydrochloride salt as described in Example 4; recrystallized fromethanol, m.p. 243.5245.5C.

Anal; Calcd. for C H N .HCl: C, 71.68; H, 6.30; N,

11.94. Found: C, 71.92; H, 6.33; N, 12.17.

. EXAMPLE 7 2-(3-lndolyl)-1-[2-(5-methyl-1-pyrrolinyl)]-indolinehydrochloride The procedure of Example 1 is repeated substituting 0.2moles of 5-methyl-2-pyrrolidone for .the 2- pyrrolidone specified inExample 1. In this. instance after the reaction period and cooling ofthe reaction mixture it is poured into 200 ml. of cold concentratedammonium hydroxide (29%) then stirred for 10 minutes before separationof the organic solvent layer. The solvent layer is dried over magnesiumsulfate and then chilled in an ice bath resulting in crystallization of10.0 g. of the desired product as the free base, m.p. 173l 78C. Thismaterial is immediately converted to its hydrochloride salt bydissolving in 100 ml. of ethanol and treating with hydrogen chloride.Approxi- "mately, 250 ml. ether is mixed with the resulting solutionresulting in crystallization of 9.6 g. of the hydrochloride salt. Thismaterial is recrystallized from a mixture of ml. of ethanol and 200 ml.of ether, yield 8.3 g. (23.6%), m.p. l94.5199.5C., dec.

Anal. Calcd. for C H N .HC1: C, 71.68; H, 6.30; N, 11.94; Cl, 10.08.Found: C, 71.69; H, 6.31; N, 11.64; Cl, 9.78.

Nuclear magnetic resonance spectrum of this hydrochloride salt usingtrifluoroacetic acid as solvent revealed the following characteristics.

The twin doublets-fen the pyrroline CH -5 together integratingfor'three-prqtp ns at 1.53 ppm and 1.47 ppm indicate that the sample isa inixture of the two possible racemic mixtures. The multiplet at 5.65ppm for the indoline H-2 rather" than the normal doublet of doublets isfurther evidence for-the presence of both racemates.

EXAMPLE 8 2-(3-Indolyl)-l-[2-(5-methyl-l-pyrrolinyl)]- indoline.

Table 5.

NMR Characteristics Example 8 Chemical Rela- Shift tive Structural 8(ppm) Area Feature Multiplicity 8.32 l indoline H-7 doublet of doublets5.75 1 indoline l-l-2 doublet of doublets (J=3.5 and 10.0 cps) 10.98 lindole NH broad singlet l 14 3 pyrroline doublet CH -5 (.l=6.2 cps)1.7-4.0 7 indoline 1+3 broad singlet pyrroline 11-3, H-4, and H-5EXAMPLE 9 2 ,3 ,5 ,6-Tetrahydro-5-( indol-3-yl )-3 ,3-dimethyl-1H-pyrrolinyl[2,1-b] 1,3]benzodiazepine A solution of 8.5 g. ofl-[2-(5,5-dimethyl-l pyrrolinyl)]-2-(3-indolyl)indoline (Example 1 l in250 ml. of n-butanol is refluxed for 63 hrs. The progress of thereaction is assayed during this period by thin layer chromatography on aglass plate coated with alumina. Small aliquots of the reaction mixtureare removed at intervals, the solvent evaporated and the residue dissolved in a small amount of chloroform containing 10% ethanol. This isused to prepare the thin layer chromatogram. For comparison a parallelchromatogram is made on the same plate from the starting material. 10-dine serves as indicator after exposure of the developed plates to anatmosphere of iodine in a closed chamber. After 65 hrs. the presence ofthe product is evident from a rather strong spot which develops at Rf2.3 as compared to the faster moving starting material which appears atRf 8.2. The product can be detected by thin layer chromatography earlyin the reaction period, at hrs., but even after 63 hrs. some of thestarting material remains. The reaction is, nevertheless, terminated andthe solvent removed by vacuum evaporation. The residue is trituratedwith 100 ml. of hot acetone and filtered from insoluble materialweighing 2.2 g. On chilling the filtrate a further 2.1 g. of material isobtained. Both portions of acetone insoluble material can be identifiedas desired product contaminated with unreacted indoline startingmaterial by examination of the infrared spectra. Absorption at 13.51:.is characteristic of the benzodiazepine compound, and differences in thedepths of the maxima in the 6.20 to 6.41,u.region are also usefulempirical guides for distinguishing indoline and diazepine compounds.The intensities of these two peaks are reversed for these two isomericstructures, the shorter wave length showing the stronger absorption forthe benzodiazepine. The foregoing samples are combined, 4.3 g. inaggregate, dissolved in 250 ml. of boiling absolute ethanol, and thedesired product recovered after crystallization, yield 3.4 g., m.p.212.5-213.5C.

Anal. Calcd. for C H N C, 80.21; H, 7.04; N, 12.75. Found: C, 80.20; H,7.04; N, 12.78.

The nuclear magnetic resonance spectrum measured indeuterodimethylsulfoxide using tetramethylsilane as reference has thefollowing characteristics:

Table 6.

NMR Characteristics Example 9 Chemical Rela- Shift tive Structural5(ppm) Area Multiplicity Feature 7.71 l doublet of doublets IO-position10.48 1 broad singlet indole Nl-l 5.38 1 doublet of doublets 5-position2.1-3.5 4 broad singlet l and 6-positions 1.02 3 singlet 3-CH: 1.31 3singlet 3-CH 1 .88 2 multiplet 2-position EXAMPLES lO-25 Additional2-(3-Indolyl)-l-substituted-indolines The products which are listed inTable 7 are prepared by adaptation of the methods of Examples 1 or 3through substitution of various other carboxamide starting materials for2-pyrrolidone on a molecular equivalent basis. One molecular proportionof triethylamine is included in the reaction mixtures of theseadditional preparations to serve as a neutralizing agent for evolvedhydrogen chloride. None of the substances shown in Table 7 is prone torearrangement on warming in ethanol to a pyrrolobenzodiazepine. Thehydrochloride salts are prepared from these products according to themethod of Example 4. Table 7 contains a tabulation of the variouscarboxamide reactants, the products, and physical properties of theproducts. In each instance the structure of the product is confirmed byexamination of the infrared absorption and nuclear magnetic resonancespectra. With respect to the latter, the chemical shifts for the H-2 and11-7 indoline protons, with the coupling constants for the former, aregiven. They illustrate the values characteristically exhibited for thesekey features in structure illucidation. Application of the method tovarious ring substituted indole dimers is illustrated in Examples 20-25.The substituted indolylindolines required as starting materials forExamples 20-25 are prepared by dimerization of the correspondinglysubstituted indole according to the following procedure.

Preparation of 5-bromo-2-(S-bromo-3-indolyl)indoline A solution ofS-bromoindole (9.8 g., 0.05 mole) in 250 m1. of dry benzene is cooled inan ice water bath while dry hydrogen chloride gas is admitted at a briskrate for a period of 1 hr. The mixture is kept in the ice water bath for1 additional hour and the product in the form of the hydrochloride saltthen collected by filtration, weight 8.5 g., m.p. l58-160C. (dec.). Thismaterial is converted to the base by agitation with a mixture of 200 ml.of ether in 10 m1. of concentrated ammoin the remainder of the1,2-dichloroethane and added in dropwise fashion to the other materialsduring a period of 45 minutes while maintaining the temperature of themixture at about 20C. The mixture is stirred lected on a filter. It isrecrystallized from 200 ml. of ethanol mixed with 200 m1. of'ether andfinally from 17.5 ml. of ethanol, yield 3.44 g. The melting point andelemental analysis of this material is reported in Table during theentire period. The cooling bath is then re- 8. moved and the mixture isallowed to warm to room Table 8 also contains a listing of analogousskatole temperature with stirring during 2% hrs. The product dimerderivatives of Formula 11 which may be prepared is then recovered bypouring the reaction mixture into according-to Example 26 from othercarboxamide rea solution of 35 g. of sodium acetate in 100 ml. of wateractants substituted for 2-pyrro11dmone. In no instance (or a similarvolume of conc. aq. NH OH, 29%) conis rearrangement of any of thesesubstances to a pyrtaining ice. The reaction is adjusted to pH 14 withporolobenzodiazepine found to occur. The indolme structassium hydroxidewhen sodium a etate olution i ture is confirmed by the downfield shiftof the indoline used above, and the product which precipitates i re- H-7nmr resonance similar to that observed in the nmr covered by filtration,9.78 g. (74%) mp. 253-254C spectra of the Formula 1 indolylindolineslisted in Table (dec.). 15 7. Due to the presence of the 3-methylsubstituent in the indoline ring of the compounds of Formula 11, the Theforegoing material is then converted to the hychemical shift for the H-2resonance of the substances drochloride salt by suspending 8.78 g.thereof in 200 is not instrumental in structure identification. The H-7ml. of ethanol containing 7 ml. of 5.3 N ethanolic hychemical shift ofthe nmr spectra, the elemental analydrogen chloride. The suspension isheated on a steam ses, and physical properties, for these compounds arebath until the hydrochloride salt forms and dissolves. also given inTable 8. In each instance the H-7 shift is The hot solution is filteredand then mixed with 200 ml. a doublet of doublets equivalent inintensity to one proof ether. The hydrochloride salt precipitates and is001- ton on integration.

Table 8 Products of Examples 26-38. Formula 11 EXAM- H-7 NMR PLE RECRYS-CHEMICAL TAL- NUM- LlZATlON ANALYSIS SHIFT BER REACT ANT PRODUCT m.p.(C.) SOLVENT alcd Found 8( ppm) 26 Z-Pyrrolidi- 3-Methy1-2-( 3-methy1-261.5-2635 ethanol C 72.21 71.97 8.3

none indo1-2-yl)-1-[2-(1- H 6.61 6.61 pyrrolinyhlindoline N 11.49 11.2527 N-Methylform- 3-Methy1-1-[(methyl- 229.5-2305 ethanol- C 70.68 70.387.68

amide imino)methyl]-2-(3- ether H 6.53 6.34 methy1indo1-2-y1)- N 12.3612.20 indoline Hydrochloride 28 N-Methylacet- 3-Methy1-1-[1-(methyl-203.5-2065 ethanol C 71.27 71.28 8.09

amide imino)ethyl]-2-(3- H 6.84 6.82 methy1indo1-2-y1)- N 11.87 11.78indoline Hydrochloride 29 e-Caprolactam 1-[7-(3.4.5.6-Tetra- 182.5-184 5ethanol- C 72.00 71.77 7.81

hydro-2H-azepinyl)]- ether H 7.50 7.49 3-methyl-2-(3-methyl- N 10.089.88 indo1-2-yl)indo1ine Hydrochloride Hemiethanolate 30 5.5-Dimethy1-1-[2-(5.5-Dimethy1-1- 225 5-227 5 ethanol- C 73.17 73.06 8.22

Z-pyrrolidinone pyrro1iny1)] -3- other H 7.16 7.25 methy1-2-(3-methy1- N10.66 10.49 indo1-2-y1)indo1ine Hydrochloride 31* 5-Methy1-2-3-methy1-2-(3-methy1- 202-204 ethanol- C 71.86 71.90 8.32

Pyrrolidinone indo1-2yl)-1-{2-(5- ether H 6.95 7.07methy1-1-pyrroliny1)] N 10.93 10.75 indoline Hydrochloride V4 Hydrate,isomer A 32* S-Methyl-Z- 3-Methy1-2-(3-methy1- 234-2365 ethanol C 72.7172.67 8.31

pyrrolldlnone indo1-2-y1)-1-[2-(5- ether H 6.90 7.01methy1-1-pyrro1iny1)] N 11.06 10.99 indoline. Hydrochloride Isomer B 33N-Cyclopentyl- 1-[(Cyclopentylimino)- 200-201 ethanol- C 73.17 73.56 755 formamide methy1]-3-methyl-2-(3- ether H 7.16 7.23methylindo1-2-y1)indo- N 10.67 10.71 line Hydrochloride 34 N-Cyclohexyl-1-[(Cyclohexylimino)- 21 1.5213.5 ethanol C 73.60 73.66 7.65

formamide methyl]-3-methyl-2- ether H 7.41 7.38 (3-methy1indo1-2-y1)- N10.30 10.24 indoline Hydrochloride 35 N-lsopropyl- 1-[(1sopropy1imino)208.5-210.5 ethanol C 71.81 72.10 8.02

formamide methy11-3-methyl-2- ether H 7.13 7.03 (3-methylindol-2-y1)- N11.42 11.54 indoline Hydrochloride 36 N-(tert-Buty1)-1-[(tert-Buty1imino) 2265-2285 ethanol- C 72.33 72.36 7.63

formamide methy1]-3-methy1-2-(3- ether H 7.39 7.41 N 1 1.00 1 1.01

methylindol-Z-yl )indoline Hydrochloride Table 8 Products of Examples26-38. Formula ll 4 Y EXAM- 1- H-7 NMR PLE RECRYS- CHEMICAL TAL- I NUM-t r LlZATlON v ANALYSIS SHIFT BER REACTANT I PRODUCT m.p.(C.) SOLVENTCalcd. Found 6(ppm) 37 N-Cycloheptyll-[(Cycloheptylirnino) 21 -2135ethanol- C 74.00 1 73.82 not examined formamidc methyll 3-methyl-2-ether H 7.64 7.69

' (3-methylindol-2-yl) N 9.96 9.88 1 indoline Hydrochloride 38N-Cyclooctyll-[(Cyclooctylimino) 206-207 ethanol- C 74.37 74.59 7.58

formamide methylI-3-methyl-2-(3- ether H 7.86 7.56 1 N 9.64 9.46

methylindol-2-yl )indo- -line Hydrochloride The products of Examples 31and 32 are isomeric racemates derived from the same experimentalpreparation. The product of Example 31 is referred to as isomer A.lsomer A was recovered by filtration after quenching theLZ-diehloroethane reaction mixture in concentrated aqueous ammoniumhydroxide as specified in Example 26. lsomer A was recrystallized fromethanol and then converted to the hydrochloride salt by treatment withethanolic hydrogen Chloride as described in Example 26. The product ofExample 32 is referred to as isomer B. It was recovered by separatingand concentrating the dichloroethane solvent layer after quenching thereaction mixture with aqueous ammonium hydroxide as described in Example26. lsomer B was first purified by recrystallization. from ethanol andthen conrert ed 'to the f hydrochloride salt in the fashion describedfor Example 26. H v

EXAMPLE 39 and the acid addition salts of said bases wherein R R ,'and Rare hydrogen, halogen, alkyl having-1 Resolutlon of to 4 carbon atoms,alkox y having 1 to'l.2 carbon enzo lazepme m o e pure an lsomers kanoylhaving 2 to 4 carbon atoms, nitro or cyano, An ethanolic solution of theproduct of Example 3 is and treated with an equivalent amount ofD-(l)-di-p-tolu- 1 and R12 are hydrogen or lower alkyl havingoyltartaric acid. 1-2,3,5,6-Tetrahydro-5-(indol-3-yl)- from 1 to 4Carbon atoms and is located in ll-l-pyrrolo-[2,1-b][1,3]benzodiazepineD-(l -di-pr -P toluoyltartrate, being less soluble, crystallizes. Re-The Compound m accordance wlth clam 6-tetrah dro-5-(indol-3- l)-lH-rrolo[2 leated recr stallizatlon from ethanol ields the ur y y W salt.m.p. 17 6.5C. (dec.) and [fl]0 l 18.6 (C= l% 3O bl[l3]benzodlazepme oran acld addmo'n Salt methanol). The filtrates are combined, basifiedwith g fig compound in accordance with claim 1 2 3 5 concentratedaqueous ammonium hydroxide, and concentrated-to recover crude free baseenriched in dr0]o[21 b][1,3]benz0diazePine" or an acid addition form.Treatment thereof with L-(d)-di-p-toluoyltarl th f taric acid inethanolic solution pure Cl-2,3,5,6- 4, The compound in accordance claim1, 2 3 5,- tetrahydro-5-(indol-3-y1)- 1 l-l-pyrrolo-l2, l-6-tetrahydro-5-(indol-3-yl)-3-methyl-ll-l-pyrrolo[2,1-

b][l,3]benzodiaz'epine L-(d)-di-p-toluoyltartrate, m.p.b][l,3]benzodiazepine. or an acid addition salt 174-175c. (dec.), [a],,=+1 19.5 c 1%, methathereofnol). The foregoing salts are converted tothe corre- The Process for the Preparation of the base of spendinghydrochloride salts by treatment with etha- 40 claim 1 which comprisesheating a base having the nolic HCl in ethanol. The d and 1 forms of2,3,5,6- mula tetrahydro-5-(indol-3-yl)-1H-pyrrolo[2, l-

b][1,3]benzodiazepine hydrochloride have the following physicalproperties.

c 1%, MP. (Corn). n iethanol) Rb d form 25|.5-253.5 81.0 1 form2525-2545 80.2 d.l form 262-264 0 5O R What is claimed is: l. A compoundselected from the group consisting of of the bases having the formula hi V R R R, R R", and R have the same meaning as in claim 2 in a proticsolvent at a temperature in the R 4 i range of from 65 to 150C. forabout 1 to hours.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE BASES HAVING THEFORMULA
 2. The compound in accordance with claim 1,2,3,5,6-tetrahydro-5-(indol-3-yl)-1H-pyrrolo(2,1-b)(1,3)benzodiazepine,or an acid addition salt thereof.
 3. The compound in accordance withclaim 1, 2,3,5,6-tetrahydro-5-(indol-3-yl)-3,3-dimethyl-1H-pyrrolo(2,1-b)(1,3)benzodiazepine, or an acid addition salt thereof.
 4. Thecompound in accordance with claim 1,2,3,5,6-tetrahydro-5-(indol-3-yl)-3-methyl-1H-pyrrolo(2,1-b)(1,3)benzodiazepine, or an acid addition salt thereof.
 5. The processfor the preparation of the base of claim 1 which comprises heating abase having the formula